Methods

• Study design: parallel, open‐label RCT

• Study duration: NS

• Study follow‐up: 27 weeks

Participants

• Country: USA

• Setting: multicentre (42 centres)

• Patients ≥ 18 years; received HD for ≥ 3 mo; were receiving either paricalcitol or doxercalciferol to manage SHPT; historical plasma PTH values between 150 and 800 pg/mL (confirmed during screening); albumin‐corrected serum total calcium concentrations ≥ 8.4 mg/dL. Patients with PTH levels between 300 to 800 pg/mL were considered without regard to serum Ca x P levels, whereas those with PTH levels between 150 to 300 pg/mL were considered only if Ca x P > 55 mg²/dL². After a 3‐wk washout period during which vitamin D therapy was withheld, PTH and calcium levels were measured again on at least 2 occasions. Patients with mean PTH values > 300 pg/mL and mean calcium levels ≥ 8.4 mg/dL qualified for study

• Number: treatment group (87); control group (86)

• Mean age ± SD (years): treatment group (57.7 ± SD 14.9); control group (59 ± 12.4)

• Sex (M/F): treatment group (52/35); control group (45/41)

• Exclusion criteria: pregnant or nursing; undergone a parathyroidectomy within the previous 3 mo; involved in any other clinical study within the past 30 d; had received cinacalcet previously

Interventions

Treatment group

• Cinacalcet

• Low dose vitamin D

• Duration: 16 weeks titration, 11 weeks maintenance

Control group

• Vitamin D

Co‐interventions: NS

Outcomes

• Simultaneously achieved a mean PTH between 150 and 300 pg/mL and a mean Ca x P value < 55 mg²/dL²

• Achieved KDOQI targets for PTH, calcium, phosphorous, and Ca x P individually

• Absolute and percentage change from baseline in values for PTH, calcium, phosphorous, and Ca x P

• Proportion with 30% reduction in PTH

Notes

• ITT: yes

• Funding: "The ACHIEVE study (Study ID Number 20050102) and the preparation of this manuscript were funded by Amgen, Inc. The authors wish to thank Nelson Erlick, DPM, MS, on behalf of Amgen Inc. and Jane Mannion, MS, Amgen Inc. for their assistance in the preparation of this manuscript (Ms Mannion is currently employed by Baxter International, Inc.)"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not used

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Not used

Incomplete outcome data (attrition bias)
All outcomes

High risk

Lost to follow‐up 24% of the patients

Selective reporting (reporting bias)

Low risk

Data available for all included outcomes

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel, open‐label RCT

• Study duration: NS

• Study follow‐up: 52 weeks

Participants

• Country: multinational

• Setting: multicentre (90 centres)

• HD ≥ 3 mo; iPTH > 300 pg/mL; serum calcium ≥ 8.4 mg/dL; serum Ca x P > 50 mg²/dL²

• Number: treatment group (180); control group (180)

• Mean age ± SD (years): treatment group (61.2 ± 12.6); control group (61.8 ± 12.8)

• Sex (M/F): treatment group (112/68); control group (95/85)

• Exclusion criteria: previous cinacalcet treatment; calcium‐free phosphate binding agents; bisphosphonate therapy; lipid lowering within 30 d; atrial fibrillation; coronary artery bypass grafting or stent; valve replacement; heart transplant; pacemaker; aortic aneurysm; parathyroidectomy within 3 mo or in next 6 mo; scheduled kidney transplant; body weight > 136 kg; inability to absorb oral medications; sensitivity to cinacalcet; unstable medical condition

Interventions

Treatment group

• Cinacalcet

• Low dose vitamin D

• Duration: 20‐week dose‐titration phase, 32‐week follow‐up phase

Control group

• Vitamin D at the same dose prescribed before randomisation

• Duration: 52 weeks

Co‐interventions

• Treatment group: vitamin D (75%); phosphate binders (calcium‐based (83%); sevelamer (26%); lanthanum (4%); other (11%))

• Control group: vitamin D (79%); phosphate binders (calcium‐based (84%); sevelamer (26%); lanthanum (7%); other (8%))

Outcomes

• % change in CAC score from baseline to week 52

• Absolute change in CAC score from baseline to week 52

• Absolute and percentage change in calcification scores for the thoracic aorta, aortic valve and mitral valve from baseline to week 52

• > 15% progression of CAC from baseline to week 52

• Absolute and percentage change in PTH, calcium, phosphorous and Ca × P from baseline to the end of study as assessed during weeks 44 to 52 of follow‐up

• Safety of cinacalcet as measured by the type, frequency and severity of adverse events and their reported relationship to treatment

• Absolute and percent changes in mean PTH, calcium, phosphorous and Ca × P values from baseline to end of study as assessed at week 44–52 in the efficacy analysis set

Notes

• ITT: yes

• Funding: "This study was sponsored by Amgen Inc. J.F. has received speaker and consultant honoraria from Amgen, Genzyme, Shire and has received grant support from Amgen and Fresenius. P.R. has received research grants from Amgen and Genzyme. G.A.B. has received research grants from Amgen, Genzyme, Shire, Novartis, DaVita, and Fresenius; has received fees for expert consultancy and/or advice from Amgen, Genzyme, Shire, Mitsubishi, and Theraclion. P.U.T. has received fees for clinical research, speaking and expert consultancy from Amgen, Shire, Novartis, Roche, Fresenius, Roche, HAS, and Hemotech. G.M.C. has received research funding from Amgen. W.G.G., N.L., G.D. and B.D. are employees and stockholders in Amgen"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label (http://clinicaltrials.gov/show/NCT00379899)

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 22.2 % patients

Selective reporting (reporting bias)

High risk

Not reported systematically (end of treatment calcium, phoshorous, PTH and adverse events)

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel RCT

• Study duration: April 2003 to October 2003

• Study follow‐up: 5 weeks

Participants

• Country: Japan

• Setting: multicentre (2 centres)

• Aged 20 to 74 years; serum iPTH ≥ 300 pg/mL, serum calcium 9.0–11.5 mg/dL; treatment with HD for at least 12 weeks before the screening period. Patients receiving vitamin D sterols or phosphate binders were required to be on a stable dose during the screening period. Dialysate calcium concentration and the size of the dialyzer membrane surface area could not be changed during the 14 days before enrolment.

• Number: treatment group (91 randomised, 79 completed); control group (30)

• Mean age ± SD (years): treatment group (56.7 ± 9.2; 55.8 ± 7.7; 53.2 ± 7.0); control group (51.8 ± 7.5)

• Sex (M/F): treatment group (54/25); control group (25/5)

• Exclusion criteria: severe hepatic diseases; cirrhosis, severe heart failure; uncontrolled hypertension; uncontrolled DM; malignant neoplasm; serious infectious diseases; undergone a parathyroidectomy within 24 weeks before enrolment; parathyroid intervention therapies (percutaneous ethanol injection therapy (PEIT) during the screening period; pregnant or lactating females

Interventions

Treatment group

• Cinacalcet: 12.5 to 50 mg/d

• Duration: 3 weeks maintenance, 2 weeks follow‐up

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (67%); phosphate binders (96%)

• Control group: vitamin D (70%); phosphate binders (100%)

Outcomes

• Percentage changes from baseline in serum iPTH levels at the end of dosing (week 3)

• Percentage changes from baseline in serum calcium, phosphorous, Ca x P and bone metabolism markers (BSAP, osteocalcin, TRACP and NTx) levels at the end of dosing

Notes

• ITT: per‐protocol analysis was used to analyse efficacy endpoints

• Three treatment groups were combined

• Funding: "This study was supported by Kirin Brewery. Drs Akizawa, Tsukamoto, Uchida, Iwasaki and Koshikawa are scientific advisors for Kirin Brewery"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Central computerised system

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Cinacalcet and placebo tablets were identical in appearance in order to maintain the double‐blind status of the study."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"All laboratory determinations, except for hematological assessments, were performed at a central laboratory"

Incomplete outcome data (attrition bias)
All outcomes

High risk

Per‐protocol analysis was used to analyse efficacy endpoints. 14.2% lost to follow‐up in the active arm. 10.7% lost to follow‐up in total

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Authors are scientific advisors for sponsor

Methods

• Study design: parallel RCT

• Study duration: December 2001 to January 2003

• Study follow‐up: 26 weeks

Participants

• Country: multinational

• Setting: multicentre (125 centres)

• Medically stable patients with secondary hyperparathyroidism; ≥ 18 years; treated with thrice‐weekly HD for at least three mo; mean plasma PTH of at least 300 pg/mL; established by 3 measurements obtained within a 30‐day screening period. Dialysate calcium levels remained unchanged throughout the study.

• Number: treatment group (371); control group (370)

• Mean age ± SD (years): treatment group (54 ± 14); control group (55 ± 15)

• Sex (M/F): treatment group (226/145); control group (229/141)

• Exclusion criteria: evidence of cancer; active infection; diseases known to cause hypercalcaemia; serum Ca < 8.4 mg/dL corrected for albumin; receiving drugs such as flecainide, thioridazine, and most tricyclic antidepressants

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 12 weeks titration, 14 weeks maintenance

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (66%); phosphate binders (92%)

• Control group: vitamin D (67%); phosphate binders (93%)

Outcomes

• Mean PTH ≤ 250 pg/mL

• Reduction from base line of at least 30% in mean PTH levels

• Percent change in the values for PTH, calcium, phosphorous, Ca x P

Notes

• Stop/endpoints: iPTH < 250 pg/mL

• ITT: no

• Pooled data from 2 studies

• Funding: "Supported by Amgen"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinded study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 22%

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Pooled data from 2 studies; statistical analyses and data interpretation by sponsor; data held by sponsor; editorial assistance from sponsor

Methods

• Study design: parallel RCT

• Study duration: June 2002 and March 2003

• Study follow‐up: 18 weeks

Participants

• Country: USA and Canada

• Setting: multicentre (16 centres)

• Men and women, ≥ 18 years with CKD and SHPT but were not receiving dialysis; GFR of 15 to 50 mL/min/1.73 m²; one iPTH < 130 pg/mL; serum Ca ≥ 9.0 mg/dL

• Number: treatment group (27); control group (27)

• Mean age ± SD (years): treatment group (60.6 ± 15.6); control group (61.9 ± 15.1)

• Sex (M/F): treatment group (16/11); control group (22/5)

• Exclusion criteria: any unstable medical condition; pregnant or lactating; undergone parathyroidectomy or experienced MI in the previous 3 months; kidney transplantation at any time; changed vitamin D therapy in the previous 30 days; were likely to begin dialysis therapy or receive a kidney transplant within 18 weeks

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 12 weeks titration, 6 weeks maintenance

Control group

• Placebo: 30 to 180 mg/d

• Duration: 12 weeks titration, 6 weeks maintenance

Co‐interventions

• Treatment group: vitamin D (22%); phosphate binders (37%)

• Control group: vitamin D (33%); phosphate binders (48%)

Outcomes

• ≥ 30% reduction from baseline in mean iPTH

• Percentage change in mean iPTH within each treatment group (efficacy)

• Collection of adverse events and laboratory parameters (safety)

Notes

• ITT: yes

• Funding: "Supported in part by a grant from Amgen Inc. WL, PSK, and LCM are employees of Amgen Inc"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Low risk

Centralised interactive voice‐response system

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinded study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 30% of patients

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel RCT

• Study duration: December 2004 to August 2006

• Study follow‐up: 32 weeks

Participants

• Country: multinational

• Setting: multicentre (73 centres)

• Adults with an iPTH ≥ 100 pg/mL (CKD stage 3) or ≥ 160 pg/mL (CKD stage 4); eGFR 15 to 59 mL/min/1.73 m²; albumin‐corrected serum calcium concentration ≥ 9.0 mg/dL

• Number: treatment group (302); control group (102)

• Mean age ± SD (years): treatment group (64.7 ± 13.3); control group (66.2 ± 12.2)

• Sex (M/F): treatment group (177/125); control group (60/42)

• Exclusion criteria: kidney transplantation; pregnancy; lactation; laboratory evidence of primary hyperparathyroidism; unstable medical condition; participation in a previous cinacalcet clinical study; likelihood of dialysis or scheduled for kidney transplantation within 28 weeks after day 1; MI within 3 months before day 1; participation in another investigational study; prior treatment with cinacalcet; change in active vitamin D sterol treatment in the previous 30 days

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 16 weeks titration, 16 weeks maintenance

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (21%); phosphate binders (19%)

• Control group: vitamin D (21%); phosphate binders (18%)

Outcomes

• Mean ≥ 30% decrease in iPTH level

• iPTH ≤ 70 pg/mL (CKD stage 3) or ≤ 110 pg/mL (CKD stage 4)

• Mean percentages of change in iPTH levels from baseline

• Adverse events

• Changes in haematology, clinical chemistry and urine calcium and phosphorous results

Notes

• ITT: no

• Funding: "The writing of this manuscript was supported by Amgen Inc; see Financial Disclosure for further information." "This trial (20000178) was sponsored by Amgen Inc, which markets cinacalcet. Dr Chonchol is a member of advisory boards for Amgen; Dr Locatelli is a member of advisory boards for Amgen‐Dompé, Shire, and Mitsubishi; Dr Charytan receives research and/or consultation support from Amgen; Dr de Francisco is a clinical advisor for Amgen and lectures for Amgen, Roche, Jansen Cilag, and Abbott; Dr Jolly is a stockholder of Amgen; Drs Albizem and Mix and Ms Kubo are employees of and stockholders of Amgen; and Dr Block is an advisor for Amgen and has received research support from Amgen."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Low risk

Interactive voice‐response system

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinded study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss to follow‐up 3% of patients

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Sponsor on authorship; sponsor involved in writing manuscript

Methods

• Study design: parallel RCT

• Study duration: July 2009 to August 2010

• Study follow‐up: 36 weeks

Participants

• Country: Kuwait; Saudi Arabia

• Setting: multicentre (2 centres)

• Adults ≥ 18 years; ESKD with SHPT; receiving maintenance HD 3 times/week for ≥ 3 months; iPTH ≥ 31.8 pmol/L; albumin‐corrected serum calcium ≥ 2.1 mmol/L; no more than 20% of the study population could have iPTH levels exceeding 84.8 pmol/L

• Number: treatment group (55); control group (27)

• Mean age ± SD (years): treatment group (51.5 ± 12.7); control group (51.8 ± 15)

• Sex (M/F): treatment group (27/28); control group (14/13)

• Exclusion criteria: any unstable medical condition; breastfeeding; experienced a MI within 3 month of study day 1; undergone a parathyroidectomy within 6 month of study day 1; gastrointestinal disorder associated with impaired absorption of oral medications or an inability to swallow tablets; received vitamin D therapy for < 21 d; change in prescribed vitamin D brand or dose within 21 d before study day 1; enrolled in other studies; previously enrolled or participated in other cinacalcet clinical studies

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 12 weeks titration, 24 weeks maintenance

Control group

• Conventional therapy

Co‐interventions

• Treatment group: vitamin D (50%); phosphate binders (86%)

• Control group: vitamin D (52%); phosphate binders (89%)

Outcomes

• Mean iPTH ≤ 31.8 pmol/L

• Both mean Ca x P < 4.44 mmol²/L² and iPTH ≤ 31.8 pmol/L

• Mean calcium < 2.37 mmol/L

• Mean phosphorous < 1.78 mmol/L

• Mean Ca x P < 4.44 mmol²/L²

• Adverse events

• Changes in safety laboratory parameters (including clinical chemistry and haematology)

Notes

• ITT: no

• Funding: NS

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss to follow‐up 5% of patients

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Uneven comparisons

Methods

• Study design: parallel RCT

• Study duration: 22 August 2006, to 31 January 2008

• Study follow‐up: treatment group (21.2 months); control group (17.5 months)

Participants

• Country: multinational (USA, Canada, Argentina, Brazil, Mexico, Australia, Austria, Belgium, Denmark, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Portugal, Russia, Spain, Sweden, Switzerland, UK)

• Setting: multicentre (approx. 500 centres)

• Men or women ≥18 years of age at screening; treated with maintenance HD 3 times/wk for ≥ 3 months before randomisation; PTH ≥ 300 pg/mL; serum calcium ≥ 8.4 mg/dL; Ca x P ≥45 mg²/dL²; available during the follow‐up phase of the study; agree to be followed for study endpoints until the end of study; appropriate written informed consent must be obtained.

• Number: treatment group (1948); control group (1935)

• Mean age ± SD: 54 ± 14 years

• Sex (M/F): treatment group (1140/808); control group (1167/768)

• Exclusion criteria: unstable medical condition; parathyroidectomy; severe concomitant disease, including life‐threatening malignancy or acquired immune deficiency syndrome, or any other life‐threatening concomitant disease; received therapy with cinacalcet within 3 months of randomisation; hospitalization within 12 weeks of randomisation for any of the following events (MI, unstable angina, heart failure, peripheral vascular disease, stroke; history of seizure within 12 weeks prior to randomisation); scheduled date for kidney transplant from a known living donor; anticipated parathyroidectomy within 6 months after randomisation; currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s); receiving other investigational agent(s); known sensitivity or intolerance to any of the products to be administered; any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures; pregnant; breast feeding; child‐bearing potential and not using adequate contraceptive precautions

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 21.2 months

Control group

• Placebo

• Duration: 17.5 months

Co‐interventions

• Treatment group: vitamin D (59.3%); phosphate binders (87.8%)

• Control group: vitamin D (59.6%); phosphate binders (89%)

Outcomes

• Composite endpoint of time to death or first nonfatal cardiovascular event (MI, hospitalisation for unstable angina, heart failure, or a peripheral vascular event)

• Time to individual components of primary composite endpoint

• Death from cardiovascular causes

• Stroke

• Bone fracture

• Parathyroidectomy

Notes

• ITT: yes

• Funding: "This study was funded by Amgen, Inc and led by an executive committee composed of academic members, two sponsor members (nonvoting), and statisticians. The executive committee oversaw the design, conduct, and all analyses. Data were collected by the sponsor and shared with the executive committee throughout the study and after unblinding. The analysis was performed by the sponsor and confirmed by an independent biostatistician at Stanford University School of Medicine. The sponsor provided the active medication and matching placebo. The lead author wrote the first draft of the manuscript, and the executive committee was responsible for data interpretation and manuscript completion. The sponsor reviewed the manuscript, but decisions about the final manuscript were made by the lead author and academic members of the executive committee only."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Generated by Amgen

Allocation concealment (selection bias)

Low risk

Interactive voice‐response system

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss to follow‐up 7.9% of patients

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Sponsor on authorship; sponsor involved in writing manuscript; sponsor held data and analysed data

Methods

• Study design: parallel RCT

• Study duration: April to December 2004

• Study follow‐up: 14 weeks

Participants

• Country: Japan

• Setting: multicentre (29 centres)

• Patients > 20 years of age with ESRD and SHPT who were undergoing HD 3 times/wk for at least 16 weeks and were in a medically stable condition; serum iPTH level ≥300 pg/mL both at 1 and 2 weeks prior to the cinacalcet administration; serum calcium level ≥ 9.0 mg/dL at 1 week prior to the cinacalcet administration

• Number: treatment group (72); control group (71)

• Mean age ± SD (years): treatment group (54.7 ± 11); control group (55.7 ± 11.7)

• Sex (M/F): treatment group (40/32); control group (37/34)

• Exclusion criteria: parathyroidectomy within 24 weeks prior to the treatment; percutaneous ethanol injection therapy into the parathyroid gland during the 4 weeks’ screening period; severe impairment of hepatic function; severe hypertension; uncontrolled DM; cancer; severe infection; severe cardiac failure

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 14 weeks

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (87.5%); phosphate binders (93.1%)

• Control group: vitamin D (88.7%); phosphate binders (95.8%)

Outcomes

• Percentage with serum iPTH levels ≤ 250 pg/mL at the end of the dosing

• Adverse events

• Laboratory variables

• Vital signs

Notes

• ITT: yes

• Funding: "This study was supported by Kirin Pharma Co., Ltd."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centralised computer system

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss to follow‐up 2.8% of patients

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Study sponsored by Kirin Parma Co. LTD

Methods

• Study design: parallel RCT

• Study duration: NS

• Study follow‐up: 24 days

Participants

• Country: USA

• Setting: multicentre

• Medically stable individuals ≥ 18 years undergoing HD 3 times/wk for at least 3 months with biochemical evidence of secondary hyperparathyroidism as judged by serum PTH levels between 300 and 1200 pg/mL; calcium levels > 9.0 mg/dL; serum phosphorous levels > 3.0 mg/dL; serum aluminium levels < 40 mg/L; serum CO₂ levels > 15 mEq/L; serum potassium concentrations < 6.2 mEq/L; HCT values > 30%; serum ferritin levels > 100 ng/mL; transferrin saturation values > 20%; urea reduction rate ≥ 65% and/or measured Kt/V values > 1.2.

• Number: treatment group (16); control group (5 randomised, 4 analysed)

• Mean age ± SD (years): treatment group (48.6 ± 12.4); control group (54.7 ± 16.8)

• Sex (M/F): treatment group (13/3); control group (1/3)

• Exclusion criteria: women of childbearing age unless they were using effective contraceptive measures or had previously been rendered sterile surgically; serum levels of hepatic transaminases or bilirubin were more than twice the upper limit of normal or if they were using medication such as selective serotonin reuptake inhibitors, tricyclic antidepressants, or B‐adrenergic blocking agents that are metabolized extensively by the P450 pathway; history of seizures; malignancy; hyperthyroidism; granulomatous diseases that could cause hypercalcaemia; MI within the previous 6 months; corrected QT interval (QTc) on electrocardiogram that exceeded 450 milliseconds

Interventions

Treatment group

• R‐568: 100 mg/d

• Duration: 15 days maintenance

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (38%); phosphate binders (31%)

• Control group: vitamin D (50%); phosphate binders (50%)

Outcomes

• Plasma PTH

• Blood‐ionized calcium

• Pharmacokinetic data

• Adverse effects

Notes

• ITT: no

• Funding: "This work was supported by Amgen, Inc., and by USPHS grants RR‐00865 and DK‐52905"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 38% of patients

Selective reporting (reporting bias)

High risk

Not reported systematically (end of treatment calcium, phoshorous, PTH and adverse events)

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel RCT

• Study duration: NS

• Study follow‐up: 16 days

Participants

• Country: USA

• Setting: multicentre

• Patients ≥ 18 years; medically stable, and had been treated for at least 3 months with thrice‐weekly HD with evidence of secondary hyperparathyroidism as judged by two plasma PTH determinations obtained at least a week apart within 21 d of the initial dose of AMG‐073 that were between 250 and 1500 pg/mL; serum total calcium values of ≥ 9.0 mg/dL after correcting for serum albumin concentrations; serum phosphorous levels of ≥ 2.5 mg/dL; serum aluminium levels < 40 ug/L; Hb level ≥ 10 g/dL or a blood HCT ≥ 30%; chest radiograph within the past 6 months showing no evidence of active parenchymal disease; body mass index between 15 and 40 kg/m²

• Number: treatment group (23); control group (7)

• Mean age ± SD: 46 ± 16 years

• Sex (M/F): NS

• Exclusion criteria: women of childbearing age unless they had previously been rendered sterile surgically for other medical reasons; serum levels of hepatic transaminases or bilirubin were more than twice the upper limit of normal; history of seizures within the past 12 months; malignancy within the past 5 years; hyperparathyroidism; MI within the previous 6 months a cardiac ventricular rhythm disturbance requiring active treatment; a gastrointestinal disorder that could affect the absorption of drugs given orally; granulomatous diseases that could cause hypercalcaemia

Interventions

Treatment group

• AMG‐073: 10 to 50 mg/d

• Duration: 8 days maintenance

Control group

• Placebo

Co‐interventions: NS

Outcomes

• Serum PTH

• Serum calcium

• Dose response

Notes

• ITT: no

• Funding: "This work was supported by Amgen Inc. and by USPHS grants DK‐52905, DK‐60107, and RR‐00865"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No patients lost to follow‐up

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel RCT

• Study duration: NS

• Study follow‐up: 12 weeks

Participants

• Country: USA

• Setting: multicentre (2 centres)

• Medically stable patients with serum calcium levels corrected for albumin concentration ≥ 8.4 mg/dL; serum phosphorous levels ≥ 3.0 mg/dL

• Number: treatment group (17); control group (5)

• Mean age ± SD (years): treatment group (48.5 ± 10.4); control group (48 ± 13.1)

• Sex (M/F): treatment group (14/3); control group (4/1)

• Exclusion criteria: NS

Interventions

Treatment group

• Cinacalcet: 25 to 300 mg/d

• Duration: 12 weeks

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (71%); phosphate binders (100%)

• Control group: vitamin D (60%); phosphate binders (80%)

Outcomes

• Pharmacodynamic data at doses > 100 mg

• Adverse effects

Notes

• ITT: no

• Funding: "From Pharmacokinetics and Drug Metabolism, Early Development, and Biostatistics, Amgen Inc, Thousand Oaks, CA; Orlando Clinical Research Center, Orlando, FL; and Clinical Research Center, New Orleans, LA"

• Not included in meta‐analyses

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 59.1% of patients

Selective reporting (reporting bias)

High risk

Not reported systematically (end of treatment calcium, phosphorous, PTH and adverse events)

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel, open‐label RCT

• Study duration: NS

• Study follow‐up: 28 weeks

Participants

• Country: multinational

• Setting: multicentre (89 centres)

• Eligible patients were aged ≥ 8 years with Stage 5 CKD receiving maintenance HD 3 times/wk for at least 3 months before screening and were to continue HD during the study; serum iPTH 130 to 700 pg/mL; total alkaline phosphatase ≥ 0 U/L; calcium ≤ 10.0 mg/dL; Ca x P ≤ 5 mg²/dL² for US centres or ≤ 70 mg²/dL² for non‐US centres; iPTH 300–800 pg/mL; calcium 8.4 to 10.0 mg/ dL; phosphorous ≤ 6.5 mg/dL

• Number: treatment group (134); control group (134)

• Mean age ± SD (years): treatment group‐IV (59.9 ± 12.0); treatment group‐oral (65.1 ± 12.5); control group‐IV (61.2 ± 12.7); control group‐oral (65.7 ± 13.5)

• Sex (M/F): treatment group‐IV (38/26); treatment group‐oral (43/27); control group‐IV (38/26); oral group‐oral (49/23)

• Exclusion criteria: allergic reaction or significant sensitivity to any study drug; expected daily requirement of > 2.0 g of oral elemental calcium; previous parathyroidectomy; chronic gastrointestinal disorders; clinically significant liver disease and use of known inhibitors or inducers of cytochrome P450 3A or of drugs metabolized by cytochrome P450 2D6 within 2 weeks before study drug administration

Interventions

Treatment group

• Cinacalcet

• Low dose vitamin D

• Duration: 28 weeks

Control group

• Vitamin D

Co‐interventions: NS

Outcomes

• Mean iPTH value of 150 to 300 pg/mL during weeks 21 to 28

• Achieved ≥ 30% or ≥ 50% reduction from baseline in iPTH

• Hypocalcaemia (mean calcium < 8.4 mg/dL) during weeks 21 to 28

• Hypercalcaemia (mean calcium > 10.5 mg/dL) during weeks 21 to 28

• BSAP

• Alkaline phosphatase

Notes

• ITT: yes

• Funding: "The IMPACT SHPT study was funded by Abbott Laboratories Inc. Writing and editorial assistance, funded by Abbott Laboratories Inc., was provided by Roland Tacke, PhD, Marsha Hall and Colleen Hedge of Scientific Connexions, Newtown, PA, USA"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Generated by Clinical Statistics department of Abbott

Allocation concealment (selection bias)

Low risk

Interactive voice‐response system

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 24.3% of patients

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Sponsor on authorship; sponsor involved in writing manuscript; sponsor held data and analysed data

Methods

• Study design: parallel RCT

• Study duration: NS

• Study follow‐up: 18 weeks

Participants

• Country: USA, Canada

• Setting: multicentre (23 centres)

• Patients ≥ 18 years, treated for at least 3 mo with HD; PTH levels ≥ 300 pg/mL despite receiving standard of care (phosphate binders and/or vitamin D sterols); serum calcium corrected for serum albumin ≥ 8.8 mg/dL and < 11.0 mg/dL; serum phosphorous ≥ 2.5 mg/dL; Ca x P < 70 mg²/dL². Patients receiving vitamin D sterols were required to be on a stable dose for at least 21 days before enrolment; dialysate calcium concentration and calcium supplements/oral phosphate binders dose could not be changed during the 7 days before enrolment

• Number: treatment group (39); control group (39)

• Mean age ± SD (years): treatment group (52.7 ± 16.4); control group (48.8 ± 15.6)

• Sex (M/F): treatment group (24/15); control group (22/17)

• Exclusion criteria: medically unstable; evidence of an active infectious or malignant process or diseases known to cause hypercalcaemia; Hb concentration < 9.0 g/dL or a HCT < 27%; liver transaminases and bilirubin levels more than twice the upper limit of normal

Interventions

Treatment group

• AMG‐073: 10 to 50 mg/d

• Duration: 12 weeks titration, 6 weeks maintenance

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (67%); phosphate binders (87%)

• Control group: vitamin D (62%); phosphate binders (87%)

Outcomes

• Reduction in PTH ≥ 30% during the maintenance phase

• Mean percent change from baseline for PTH, serum calcium, phosphorous, and Ca x P during the maintenance phase

• Adverse events

• Laboratory variables (haematology and biochemistry)

• Vital signs

Notes

• ITT: no

• Funding: "Funding for this study was provided by Amgen Inc"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 14.1% of patients

Selective reporting (reporting bias)

High risk

Not reported systematically (end of treatment calcium, phosphorous, PTH and adverse events)

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel RCT

• Study duration: May 2002 to March 2003

• Study follow‐up: 26 weeks

Participants

• Country: multinational

• Setting: multicentre (60 centres)

• Age ≥18 years; mean of two plasma iPTH values ≥ 300 pg/mL; mean of two serum calcium values ≥ 8.4 mg/dL during the screening phase; treatment with HD, continuous ambulatory PD, or automated PD for at least 1 mo before beginning study medication; patients who were receiving vitamin D therapy must have been treated with a stable dose for at least 30 d before enrolment

• Number: treatment group (294); control group (101)

• Mean age ± SD (years): treatment group (51.8 ± 14.0); control group (53.5 ± 13.9)

• Sex (M/F): treatment group (181/113); control group (64/37)

• Exclusion criteria: an unstable medical condition; undergone parathyroidectomy; MI within 3 mo before the study began

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 16 weeks titration, 10 weeks maintenance

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (65%); phosphate binders (NS)

• Control group: vitamin D (69%); phosphate binders (NS)

Outcomes

• Mean iPTH level ≤ 250 pg/mL

• Reduction in iPTH of at least 30% from baseline

• Mean percentage changes from baseline for iPTH, serum calcium, phosphorous, and Ca x P

• Mean iPTH ≤ 300 pg/mL or reductions in iPTH of a least 20%, 40%, or 50% from baseline

• Ca x P < 55 mg²/dL²

• Mean reduction in Ca x P of at least 5 or 10 mg²/dL²

Notes

• ITT: yes

• Funding: "This study was supported by Amgen Inc. Holly Brenza Zoog assisted in the preparation of the manuscript."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Programmatic algorithm

Allocation concealment (selection bias)

Low risk

Interactive voice‐response system

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 25.3% of patients

Selective reporting (reporting bias)

High risk

Not reported systematically (end of treatment calcium, phosphorous, PTH and adverse events)

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel RCT

• Study duration: October 2001 to May 2003

• Study follow‐up: 52 weeks

Participants

• Country: multinational

• Setting: multicentre (17 centres)

• Medically stable patients ≥ 18 years who had received HD for ≥ 1 month with biochemical evidence of elevated PTH levels; albumin‐adjusted serum calcium concentration ≥ 8.4 mg/dL; either Hb level > 9.0 g/dL or a HCT value > 27%; patients receiving vitamin D sterols had to have been on a constant dose for ≥ 30 days before beginning the study

• Number: treatment group (19); control group (13)

• Mean age ± SD (years): treatment group (50.3 ± 13.3); control group (51.5 ± 14.1)

• Sex (M/F): treatment group (12/7); control group (9/4)

• Exclusion criteria: received bisphosphonate or fluoride during the preceding 90 days

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 24 weeks titration, 28 weeks maintenance

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (47%); phosphate binders (100%)

• Control group: vitamin D (54%); phosphate binders (77%)

Outcomes

• Interval changes in activation frequency, bone formation rate/bone surface, number of osteoblasts and osteoclasts/bone perimeter, fibrosis surface/bone surface and woven osteoid surface/bone surface

• Absolute and percentage changes from baseline in iPTH, BSAP, NTx and Ca x P

Notes

• ITT: no

• Funding: "This study was supported by Amgen Inc (Study 20010141)"

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer generated

Allocation concealment (selection bias)

Low risk

Interactive voice‐response system

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 31.3% of patients

Selective reporting (reporting bias)

High risk

Not reported systematically (end of treatment calcium, posphorous, PTH and adverse events)

Other bias

High risk

Sponsor authorship

Methods

• Study design: parallel, open‐label RCT

• Study duration: NS

• Study follow‐up: 23 weeks

Participants

• Country: Europe

• Setting: multicentre (111 centres)

• Patients ≥ 18 years with ESKD with SHPT and had required maintenance dialysis for ≥ 1 mo; iPTH ≥ 300 pg/mL and < 800 pg/mL; bio‐intact PTH ≥150 pg/mL and < 410 pg/mL; albumin‐corrected serum calcium ≥ 8.4 mg/dL

• Number: treatment group (368); control group (184)

• Mean age ± SD (years): treatment group (58.5 ± 14.5); control group (58.3 ± 14.5)

• Sex (M/F): treatment group (224/144); control group (117/67)

• Exclusion criteria: any unstable medical condition; breastfeeding; MI within 3 mo of study day 1; parathyroidectomy within 6 mo of study day 1; gastrointestinal disorder associated with impaired absorption of oral medications or an inability to swallow tablets; patients who received vitamin D therapy for < 21 d or had a change in their prescribed vitamin D brand or dose within 21 d before study day 1; enrolled in other studies; previously enrolled or participated in other cinacalcet clinical studies

Interventions

Treatment group

• Cinacalcet: 30 to 180 mg/d

• Duration: 16 weeks titration, 7 weeks maintenance

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (68%); phosphate binders (92%)

• Control group: vitamin D (68%); phosphate binders (90%)

Outcomes

• Mean iPTH ≤ 300 pg/mL

• Both mean Ca x P < 55 mg²/dL² and iPTH ≤ 300 pg/mL

• Mean Ca × P < 55 mg²/dL²

• Man calcium < 9.5 mg/dL

• Mean phosphorous < 5.5 mg/dL

Notes

• ITT: yes

• Funding: "This study was sponsored by Amgen Inc."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Unclear risk

NS

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

High risk

Loss to follow‐up 21.9% of patients

Selective reporting (reporting bias)

Low risk

All the prespecified outcomes were reported

Other bias

High risk

Sponsor on authorship

Methods

• Study design: parallel RCT

• Study duration: NS

• Study follow‐up: 18 weeks

Participants

• Country: USA

• Setting: multicentre (17 centres)

• Patients ≥ 18 years treated for at least 3 mo with HD and had uncontrolled SHPT (mean PTH ≥ 300 pg/mL, despite availability of standard care (phosphate binders and/or vitamin D sterols)); serum calcium ≥ 8.8 mg/dL and < 11.0 mg/dL; serum phosphorous ≥ 2.5 mg/dL; Ca x P < 70 mg²/dL²; patients receiving vitamin D sterols must have been on a stable dose for at least 21 d before enrolment; dialysis calcium concentration, the dose of any supplements, and the dose of oral phosphate binders must not have been changed during the 7 d before enrolment

• Number: treatment group (36); control group (35)

• Mean age ± SD (years): treatment group (49.6 ± 8.5); control group (47.9 ± 14.2)

• Sex (M/F): treatment group (27/9); control group (17/18)

• Exclusion criteria: medically unstable; evidence of an active infectious; malignant process; diseases known to cause hypercalcaemia; Hb concentration < 9.0 g/dL or a HCT < 27%; liver transaminases and bilirubin concentrations more than twice the upper limit of normal

Interventions

Treatment group

• AMG‐073: 25 to 100 mg/d

• Duration: 12 weeks titration, 6 weeks maintenance

Control group

• Placebo

Co‐interventions

• Treatment group: vitamin D (61%); phosphate binders (100%)

• Control group: vitamin D (69%); phosphate binders (94%)

Outcomes

• Mean reduction in PTH of ≥ 30% during the maintenance phase

Notes

• Stop/end point: iPTH reduction = 30%

• ITT: yes

• Funding: "Funding for this study was provided by Amgen Inc."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

NS

Allocation concealment (selection bias)

Low risk

Interactive voice‐response system

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double blinded

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

NS

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Loss to follow‐up 8.5% of patients

Selective reporting (reporting bias)

High risk

Not reported systematically (end of treatment calcium, phosphorous, PTH and adverse events)

Other bias

High risk

Sponsor on authorship